GROWTH FACTOR-STIMULATED MAP KINASE INDUCES RAPID RETROPHOSPHORYLATION AND INHIBITION OF MAP KINASE KINASE (MEK1)

The MAP kinase module (Raf/MAPKKK-MAPKK-MAPK) has been shown to be seq uentially activated after mitogenic stimulation. Here we demonstrate, by site directed mutagenesis, that MAPK is able to retrophosphorylate its own activator, MAPKK, on two threonine residues Thr-292 and Thr-38 6 in vitro, and that these sites are also phosphorylated in vivo. A co mparison of the kinetics of serum-mediated activation of a wild-type M APKK and of a mutant unable to undergo phosphorylation by MAPK suggest s that this retrophosphorylation may be involved in a negative feedbac k control of the cascade in vivo.